US3734949A - Carbamates of norbornanes - Google Patents
Carbamates of norbornanes Download PDFInfo
- Publication number
- US3734949A US3734949A US00043207A US3734949DA US3734949A US 3734949 A US3734949 A US 3734949A US 00043207 A US00043207 A US 00043207A US 3734949D A US3734949D A US 3734949DA US 3734949 A US3734949 A US 3734949A
- Authority
- US
- United States
- Prior art keywords
- dimethanol
- norbornene
- norbornanol
- benzene
- norbornanes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000002847 norbornane derivatives Chemical class 0.000 title description 3
- 150000004657 carbamic acid derivatives Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 abstract description 8
- IGHHPVIMEQGKNE-UHFFFAOYSA-N [3-(hydroxymethyl)-2-bicyclo[2.2.1]hept-5-enyl]methanol Chemical compound C1C2C=CC1C(CO)C2CO IGHHPVIMEQGKNE-UHFFFAOYSA-N 0.000 abstract description 7
- 230000000840 anti-viral effect Effects 0.000 abstract description 5
- ZQTYQMYDIHMKQB-UHFFFAOYSA-N exo-norborneol Chemical compound C1CC2C(O)CC1C2 ZQTYQMYDIHMKQB-UHFFFAOYSA-N 0.000 abstract description 5
- 229940112021 centrally acting muscle relaxants carbamic acid ester Drugs 0.000 abstract description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical class NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- -1 carbamoyloxy Chemical group 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 241000991587 Enterovirus C Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- YSVZGWAJIHWNQK-UHFFFAOYSA-N [3-(hydroxymethyl)-2-bicyclo[2.2.1]heptanyl]methanol Chemical compound C1CC2C(CO)C(CO)C1C2 YSVZGWAJIHWNQK-UHFFFAOYSA-N 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZQTYQMYDIHMKQB-VQVTYTSYSA-N (1r,3s,4s)-bicyclo[2.2.1]heptan-3-ol Chemical compound C1C[C@@H]2[C@@H](O)C[C@H]1C2 ZQTYQMYDIHMKQB-VQVTYTSYSA-N 0.000 description 1
- LWHKUVOYICRGGR-UHFFFAOYSA-N 3-bicyclo[2.2.1]heptanylmethanol Chemical compound C1CC2C(CO)CC1C2 LWHKUVOYICRGGR-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- TZLWRLOYRRZECT-UHFFFAOYSA-N bicyclo[2.2.1]hept-5-ene-2,3-diol Chemical compound C1C2C(O)C(O)C1C=C2 TZLWRLOYRRZECT-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
Definitions
- compositions of matter classified in the art of chemistry as carbamic acid esters of norbornane derivatives, which exhibit antiviral activity in standard pharmacological tests.
- R is hydrogen, carbamoyloxy or carbamoyloxymehyl; R is carbamoyloxymethyl or carbamoyloxy; and W represents a double bond or single bond, provided that when W represents a double bond and R is hydrogen, R must be carbamoyloxymethyl; and that when R is a group other than hydrogen, R and R are similar.
- compositions of matter possess the inherent general physical properties of being high melting, white crystalline solids; are substantially insoluble in water; are soluble in polar solvents such as dimethysulfoxide and dimethylformamide.
- the aforementioned physical characteristics taken together with the nature of the starting materials and the modes of synthesis, positively confirm the structure of the compositions sought to be patented.
- compositions possess the inherent applied use characteristics of exerting antiviral activity in mice infected wth Columbia SK polio virus.
- the antiviral activity is elicited by following the test procedure described by GP. Hegarty et al. on pp. 469 and 470 in an article published in Annals of the New York Academy of Science, 131, 469 (1965).
- the compounds produce a significant increase in mean survival time of mice infected with Columbia SK polio virus at a dose of 0.3 mg. per kilogram of body weight.
- the carbamic acid esters (IV) of the present invention are prepared by a two-step process which involves first treating an alcohol (II) with phosgene in an inert organic solvent, preferably benzene, at a temperature of from about 25 to 35 to afford an acid chloride ester (III), and then reacting the acid chloride ester with ammonia in an inert organic solvent at 0 to 10. These reactions are illustrated as follows:
- dicarbamates can be prepared in a similar manner from a dialcohol (V) using stoichiometrically equivalent amounts of phosgene and ammonia, as illustrated below:
- EXAMPLE 1 2-norbornanol, carb amate
- a solution of 0.225 mole of phosgene in benzene (179 ml. of a 12.5% solution, 22.3 g.) is added dropwise to a stirred solution of 16.8 g. exo-norbornanol (0.15 mole) in 300 ml. of benzene with maintenance of the temperature 30i5.
- the solution is stirred for another hour, aerated with nitrogen for 4 hours, concentrated to an oil in vacuo, and made up to the original volume with benzene.
- Ammonia gas is then passed into the reaction mixture for 18 hours at 10", and the mixture is left to stand overnight to lose ammonia.
- the precipitated ammonium chloride is filtered off, and the filtrate concenerated to a gelatinous mass which is centrifuged to yield 7.4 g. of exo-Z- norbornanol, carbamate (32% yield) after drying on a clay block in vacuo over silica gel, M.P. 91-94".
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
CARBAMIC ACID ESTERS OF 2-NORBORNANOL, 5-NORBORNENE2,3-DIMETHANOL, AND RELATED COMPOUNDS EXHIBIT ANTIVIRAL ACTIVITY.
Description
United States Patent O 3,734,949 CARBAMATES F NORBORNANES Harvey E. Album, West Chester, and William Dvonch, Radnor, Pa., assignors to American Home Products Corporation, New York, NY.
No Drawing. Continuation-impart of application Ser. No. 644,089, June 7, 1967. This application June 3, 1970, Ser. No. 43,207
Int. Cl. C07c 125/04 US. Cl. 260-482 B 2 Claims ABSTRACT OF THE DISCLOSURE Carbamic acid esters of 2-norbornanol, S-norbornene- 2,3-dimethanol, and related compounds exhibit antiviral activity.
CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of Ser. No. 644,089, filed June 7, 1967, now abandoned.
BACKGROUND OF THE INVENTION This invention relates to compositions of matter classified in the art of chemistry as carbamic acid esters of norbornane derivatives, which exhibit antiviral activity in standard pharmacological tests.
SUMMARY OF THE INVENTION The invention sought to be patentded as a composition of matter resides in the concept of a chemical compound selected from the group represented by Formula I:
wherein R is hydrogen, carbamoyloxy or carbamoyloxymehyl; R is carbamoyloxymethyl or carbamoyloxy; and W represents a double bond or single bond, provided that when W represents a double bond and R is hydrogen, R must be carbamoyloxymethyl; and that when R is a group other than hydrogen, R and R are similar.
The tangible embodiments of the compositions of matter possess the inherent general physical properties of being high melting, white crystalline solids; are substantially insoluble in water; are soluble in polar solvents such as dimethysulfoxide and dimethylformamide. Examination of compounds produced according to the hereinafter described process reveals, upon infrared spectrographic analysis, spectral data confirming the molecular structure hereinbefore set forth. For example, the C=O frequency characteristic of a carbamate ester is evident. The aforementioned physical characteristics, taken together with the nature of the starting materials and the modes of synthesis, positively confirm the structure of the compositions sought to be patented.
The tangible embodiments of the compositions possess the inherent applied use characteristics of exerting antiviral activity in mice infected wth Columbia SK polio virus. The antiviral activity is elicited by following the test procedure described by GP. Hegarty et al. on pp. 469 and 470 in an article published in Annals of the New York Academy of Science, 131, 469 (1965). The compounds produce a significant increase in mean survival time of mice infected with Columbia SK polio virus at a dose of 0.3 mg. per kilogram of body weight.
The manner of making the invention will now be generally described so as to enable a person skilled in the art of chemistry to make a specific embodiment of the same as follows:
3,734,949 Patented May 22, 1973 ice DESCRIPTION OF PREFERRED EMBODIMENTS The carbamic acid esters (IV) of the present invention are prepared by a two-step process which involves first treating an alcohol (II) with phosgene in an inert organic solvent, preferably benzene, at a temperature of from about 25 to 35 to afford an acid chloride ester (III), and then reacting the acid chloride ester with ammonia in an inert organic solvent at 0 to 10. These reactions are illustrated as follows:
0 o 0 OH ii H 010 or G1 NHQ II III IV The dicarbamates (VI) can be prepared in a similar manner from a dialcohol (V) using stoichiometrically equivalent amounts of phosgene and ammonia, as illustrated below:
i -CH2OO 01 2NHal The best mode contemplated by the inventors of carrying out their invention will now be set forth as follows:
EXAMPLE 1 2-norbornanol, carb amate A solution of 0.225 mole of phosgene in benzene (179 ml. of a 12.5% solution, 22.3 g.) is added dropwise to a stirred solution of 16.8 g. exo-norbornanol (0.15 mole) in 300 ml. of benzene with maintenance of the temperature 30i5. The solution is stirred for another hour, aerated with nitrogen for 4 hours, concentrated to an oil in vacuo, and made up to the original volume with benzene. Ammonia gas is then passed into the reaction mixture for 18 hours at 10", and the mixture is left to stand overnight to lose ammonia. The precipitated ammonium chloride is filtered off, and the filtrate concenerated to a gelatinous mass which is centrifuged to yield 7.4 g. of exo-Z- norbornanol, carbamate (32% yield) after drying on a clay block in vacuo over silica gel, M.P. 91-94".
Analysis for C H N0 .Calculated (percent): C, 61.92; H, 8.44; N, 9.02. Found (percent): C, 61.88; H, 8.19; N, 8.73.
OH2OH OHzOH EXAMPLE 2 Z-norbornanemethanol, carbamate Following the procedure of Example 1, but substituting an equivalent amount of 2-norbornanemethanol for 2- norbornanol, there is obtained the title compound.
EXAMPLE 3 5-norbornene-2,3-dimethanol, dicarbamate A solution of 0.450 mole of phosgene in benzene is added dropwise to a stirred solution of 0.15 mole of 5- norbornene-2,3-dimethanol in 300 ml. of benzene with maintenance of the temperature at 30:5. The solution is stirred for an additional hour, aerated with nitrogen for 4 hours, concentrated in vacuo, and then benzene is added to return it to the original volume. Ammonia gas is then passed into the reaction mixture for 8 hours at 10", and the mixture is permitted to stand overnight. The precipitate formed is washed with water and the residue is recrystallized from acetone to yield 18% of 5- norbornene-Z,S-dimethanol, dicarbamate, M.P. 130-136".
Analysis for C I-I N O .Calculated (percent): C, 55.0; H, 6.7; N, 11.7. Found (percent): C, 55.4; H, 6.7; N, 10.7.
EXAMPLE 4 2,3-norbornanedimethanol, carbamate Following the procedure of Example 3, but substituting an equivalent amount of 2,3-norbornanedimethanol for 5-norbornene-2,3-dimethanol, there is obtained the title compound.
EXAMPLE 5 5-norbornene-2,3-diol, dicarbamate Following the procedure of Example 3, but substituting an equivalent amount of 5-norb0rnene-2,3-di0l for 5- norbornene-2,3-dimethanol, there is obtained the title product.
EXAMPLE 6 Norbornane-2,3-dio1, dicarbamate Following the procedure of Example 3, but substituting an equivalent amount of norbornane-2,3-di0l for 5-norbornene-2,3-dimethanol, there is obtained the title compound.
All temperatures expressed herein are in centigrade.
The subject matter which the applicants regard as their invention is particularly pointed out and distinctly claimed as follows:
1. 2-norbornanol, carbamate.
2. 5-norbornene-2,3-dimethanol, dicarbamate.
References Cited UNITED STATES PATENTS 2,846,465 8/1958 Boehme et a1. 260482 3,418,362 12/1968 Goonewardene, et al. 260482 2,841,485 12/1958 Johnson, et a1. 260482 X FOREIGN PATENTS 192,795 10/1967 U.S.S.R. 260482 LORRAINE A. WEINBERGER, Primary Examiner P. I. KILLOS, Assistant Examiner US. Cl. X.R.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4320770A | 1970-06-03 | 1970-06-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3734949A true US3734949A (en) | 1973-05-22 |
Family
ID=21926036
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US00043207A Expired - Lifetime US3734949A (en) | 1970-06-03 | 1970-06-03 | Carbamates of norbornanes |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3734949A (en) |
-
1970
- 1970-06-03 US US00043207A patent/US3734949A/en not_active Expired - Lifetime
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